This invention relates to compounds having pharmacological activity, to compositions containing these compounds, and to a medical method of treatment employing the compounds and compositions. More particularly, this invention concerns certain 1H-4(5)-substituted imidazole derivatives and their salts or solvates. These compounds have H3 histamine receptor antagonist activity. This invention also relates to pharmaceutical compositions containing these compounds, and to a method of treating disorders in which histamine H3 receptor blockade is beneficial.
Histamine is a chemical messenger involved in various complex biological actions. When released, histamine interacts with specific macromolecular receptors on the cell surface or within a target cell to elicit changes in many different bodily functions. Various cell types including smooth muscle, blood cells, cells of the immune system, endocrine and exocrine cells as well as neurons respond to histamine by stimulating the formation of intracellular signals, including formation of phosphatidylinositol or adenylate cyclase. Evidence that histamine plays a role as a neurotransmitter was established by the mid to late 1970""s (Schwartz, 1975) Life Sci. 17: 503-518. Immunohistochemical studies identified histaminergic cell bodies in the tuberomammillary nucleus of the posterior hypothalamus with widespread projections in the dicencephalon and telencephalon (Inagaki et al., 1988) J. Comp. Neurol. 273: 283-300.
Identification of two histamine receptors (H1 and H2) was reported to mediate the biochemical actions of histamine on neurons. Recently, studies have demonstrated the existence of a third subtype of histamine receptor, the histamine H3 receptor (Schwartz et al., 1986) TIPS 8: 24-28. Various studies have now demonstrated that histamine H3 receptors are found on the histaminergic nerve terminals in the brains of several species, including man (Arrang et al., 1983) Nature 302: 832-837. The H3 receptor found on the histaminergic nerve terminal was defined as an autoreceptor and could intimately control the amount of histamine released from the neurons. Histamine, the natural compound, was capable of stimulating this autoreceptor but when tested against known H1 and H2 receptor agonists and antagonists, a distinct pharmacological profile emerged. Further, H3 receptors have been identified on cholinergic, serotoninergic and monoamine nerve terminals in the peripheral nervous system (PNS) and central nervous system including the cerebral cortex and cerebral vessels. These observations suggest that H3 receptors are uniquely located to modulate histamine as well as other neurotransmitter release, and H3 antagonists could be important mediators of neuronal activity.
As stated, CNS histaminergic cell bodies are found in the magnocellular nuclei of the hypothalamic mammillary region and these neurons project diffusely to large areas of the forebrain. The presence of histaminergic cell bodies in the tuberomamillary nucleus of the posterior hypothalamus, a brain area involved in the maintenance of wakefulness, and their projections to the cerebral cortex suggest a role in modulating the arousal state or sleep-wake. The histaminergic projection to many limbic structures such as the hippocampal formation and the amygdaloid complex suggest roles in functions such as autonomic regulation, control of emotions and motivated behaviors, and memory processes.
The concept that histamine is important for the state of arousal, as suggested by the location of histaminergic pathways, is supported by other types of evidence. Lesions of the posterior hypothalamus is well known to produce sleep. Neurochemical and electrophysiological studies have also indicated that the activity of histaminergic neurons is maximal during periods of wakefulness and is suppressed by barbiturates and other hypnotics. Intraventricular histamine induces the appearances of an arousal EEG pattern in rabbits and increased spontaneous locomotor activity, grooming and exploratory behavior in both saline and pentobarbital-treated rats.
In contrast, a highly selective inhibitor of histidine decarboxylase, the sole enzyme responsible for histamine synthesis, has been shown to impair waking in rats. These data support the hypothesis that histamine may function in modulating behavioral arousal. The role of the H3 receptor in sleep-waking parameters has been recently demonstrated (Lin et al., 1990) Brain Res. 529: 325-330. Oral administration of RAMHA, a H3 agonist, caused a significant increase in deep slow wave sleep in the cat. Conversely, thioperamide, a H3 antagonist, enhanced wakefulness in a dose-dependent fashion. Thioperamide has also been shown to increase wakefulness and decrease slow wave and REM sleep in rats. These findings are consistent with in vivo studies demonstrating that thioperamide caused an increase in synthesis and release of histamine. Together, these data demonstrate that selective H3 antagonists may be useful in the treatment of arousal states and sleep disorders.
Serotonin, histamine, and acetylcholine have all been demonstrated to be diminished in the Alzheimer""s (AD) brain. The histamine H3 receptor has been demonstrated to regulate the release of each of these neurotransmitters. An H3 receptor antagonist would therefore be expected to increase the release of these neurotransmitters in brain. Since histamine has been demonstrated to be important in arousal and vigilance, H3 receptor antagonists might enhance arousal and vigilance via increasing levels of neurotransmitter release and improve cognition. Thus, the use of H3 receptor antagonists in AD, attention deficit hyperactive disorders (ADHD), age-related memory dysfunction and other cognitive disorders would be supported.
H3 receptor antagonists may be useful in treating several other CNS disorders. It has been suggested that histamine may be involved in the control of sleep/wake states as well as states of arousal and alertness, cerebral circulation, energy metabolism, and hypothalmic hormone secretion. Recent evidence has indicated the possible use of H3 antagonists in the treatment of epilepsy. Work has demonstrated an inverse correlation between the duration of clonic convulsions and brain histamine levels. Thioperamide, a H3 antagonist, was also shown to significantly and dose-dependently decrease the durations of every convulsive phase after electrically-induced convulsions and increase the electroconvulsive threshold.
In spite of their low density, H3 receptor binding sites can be detected outside the brain. Several studies have revealed the presence of H3 heteroreceptors in the gastrointestinal tract, as well as upon neurons of the respiratory tract. Accordingly, an H3 receptor antagonist may be useful in the treatment of diseases and conditions such as asthma, rhinitis, airway congestion, inflammation, hyper and hypo motility and acid secretion of the gastrointestinal tract. Peripheral or central blockade of H3 receptors may also contribute to changes in blood pressure, heart rate and cardiovascular output and could be used in the treatment of cardiovascular diseases.
U.S. Pat. No. 4,707,487 discloses compounds of the general formula: 
in which R1 denotes H, CH3, or C2H5, R denotes H or R2 and R2 denotes an alkyl, piperonyl, 3-(1-benzimidazolonyl)-propyl group; a group of formula: 
in which n is 0, 1, 2, or 3, X is a single bond or alternatively xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or 
and R3 is H, CH3, F, CN or an acyl group; or alternatively a group of formula: 
in which Z denotes an O or S atom or a divalent group NH, Nxe2x80x94CH3, or Nxe2x80x94CN, and R5 denotes an alkyl group, a cycloalkyl group which can bear a phenyl substituent, a phenyl group which can bear a CH3 or F substituent, a phenylalkyl (C1-C3) group or a naphthyl, adamantyl, or p-toluenesulphonyl group. It is also disclosed that these compounds antagonize the histamine H3 receptors and increase the rate of renewal of cerebral histamine.
WO 92/15567 discloses compounds of general formula: 
wherein: Z is a group of formula (CH2)m, wherein m=1-5 or a group of the formula: 
wherein R6=(C1-C3) alkyl, R7=(C1-C3) alkyl; X represents S, NH, or CH2; R1 represents hydrogen, (C1-C3) alkyl-, aryl (C1-C10) alkyl-, wherein aryl may optionally be substituted, aryl, (C5-C7) cycloalkyl, (C1-C10) alkyl-, or a group of the formula: 
wherein n=1-4, R6 is aryl, aryl (C1-C10) alkyl-, (C5-C7) cycloalkyl- or C5-C7) cycloalkyl (C1-C10) alkyl-, and R6 is hydrogen, (C1-C10) alkyl- or aryl; R2 and R5 represent hydrogen, (C1-C3) alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substituted; R3 represents hydrogen, (C1-C3) alkyl, aryl, or arylalkyl-, wherein aryl may be substituted; and R4 represents hydrogen, amino-, nitro-, cyano-, halogen-, (C1-C3) alkyl, aryl, or arylalkyl-, wherein aryl may optionally be substituted; wherein aryl is phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl or substituted pyridyl. These compounds are reported to have agonistic or antagonistic activity on the histamine H3 receptor.
U.S. Pat. No. 5,217,986 discloses compound of formula: 
This compound is reported to be active in an H3 receptor assay, is reported to be an H3 antagonist on guinea pig ileum, and accordingly is said to be useful in the treatment of diseases and conditions such as asthma, rhinitis, airway congestion, inflammation, cardiac arrhythmias, hypertension, hyper and hypo motility and acid secretion of the gastrointestinal tract, hypo- and hyper-activity of the central nervous system, migraine, and glaucoma.
WO 93/14070 discloses compounds of general formula: 
Chain A represents a hydrocarbon chain, saturated or unsaturated, of 1-6 carbon atoms in length; X represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94N(alkyl)COxe2x80x94, xe2x80x94NHCONHxe2x80x94, xe2x80x94NHxe2x80x94CSxe2x80x94NHxe2x80x94, xe2x80x94NHCSxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, OCONHxe2x80x94, xe2x80x94OCON(alkyl)-, xe2x80x94OCONHxe2x80x94COxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94CON(alkyl)-, xe2x80x94SOxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CHOHxe2x80x94, xe2x80x94NRxe2x80x94C(xe2x95x90NRxe2x80x3)xe2x80x94NRxe2x80x2xe2x80x94, R and Rxe2x80x2 can be hydrogen or alkyl and Rxe2x80x3 is hydrogen or cyano, or COY1, Y1 is alkoxy radical. Chain B represents an alkyl group xe2x80x94(CH2)nxe2x80x94, n=0-5 or an alkyl chain of 2-8 carbon atoms interrupted by an oxygen or sulfur atom or a group like xe2x80x94(CH2)nxe2x80x94Oxe2x80x94 or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94 wherein n=1 or 2. Y represents (C1-C8) alkyl, (C3-C6) cycloalkyl, bicycloalkyl, aryl, cycloalkenyl, heterocycle.
U.S. Pat. No. 5,290,790 discloses compounds of the same general structure as U.S. Pat. No. 4,707,487: 
but specifically includes amides wherein R2 is COxe2x80x94NRxe2x80x2Rxe2x80x3 and Rxe2x80x2Rxe2x80x3 are independently selected from the group consisting of (a) hydrogen; (b) phenyl or substituted phenyl; (c) alkyl; (d) cycloalkyl; and (e) alkylcycloalkyl such as cyclohexylmethyl or cyclopentylethyl.
The present invention provides, in its principal aspect, compounds of the general formula: 
where
A is xe2x80x94NHCOxe2x80x94, xe2x80x94N(CH3)xe2x80x94COxe2x80x94, xe2x80x94NHCH2xe2x80x94, xe2x80x94N(CH3)xe2x80x94CH2xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94COCH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH(OH)CH2xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94;
X is H, CH3, NH2, NH(CH3), N(CH3)2, OH, OCH3 or SH;
R2 is hydrogen or a methyl or ethyl group;
R3 is hydrogen or a methyl or ethyl group;
n is 0, 1, 2, 3, 4, 5 or 6; and
R1 is selected from the group consisting of (a) alkyl; (b) C3 to C8 cycloalkyl; (c) phenyl or substituted phenyl; (d) heterocyclic; (e) decahydronaphthalene and (f) octahydroindane; or
R1 and X may be taken together to denote a 5,6 or 6,6 saturated bicyclic ring structure when X is NH, O, or S.
The pharmaceutically acceptable salts, and individual stereoisomers of compounds of structural formula (1.0) above, as well as mixtures thereof, are also contemplated as falling within the scope of the present invention.
This invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier in combination with an effective amount of a compound of formula (1.0). The present invention also provides a method of treating conditions of therapeutic importance such as allergy, inflammation, cardiovascular disease (i.e. hyper or hypotension), gastrointestinal disorders (acid secretion, motility), cancer, bacterial, viral or fungal disorders as well as CNS disorders involving attention or cognitive disorders, (i.e., Alzheimer""s, Attention Deficit Hyperactive Disorder, age-related memory dysfunction, stroke, etc), CNS psychiatric or motor disorders (i.e., depression, schizophrenia, obsessive-compulsive disorders, tourette""s syndrome, etc.) and CNS sleep disorders (i.e., narcolepsy, sleep apnea, insomnia, disturbed biological and circadian rhythms, hyper and hyposomnolence, and related sleep disorders), epilepsy, hypothalamic dysfunction (i.e., eating disorders such as obesity, anorexia/bulimia, thermoregulation, hormone release) comprising administering an effective amount of a compound of formula (1.0) to a patient in need of such treatment.

For compounds of formula (1.0), R2 and R3 are H, methyl or ethyl;
A is xe2x80x94NHCOxe2x80x94, xe2x80x94N(CH3)xe2x80x94COxe2x80x94, xe2x80x94NHCH2xe2x80x94, xe2x80x94N(CH3)xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94COCH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH(OH)CH2xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94;
X is H, CH3, NH2, NH(CH3), N(CH3)2, OH, OCH3, or SH;
R2 is hydrogen or a methyl or ethyl group;
R3 is hydrogen or a methyl or ethyl group;
n is 0, 1, 2, 3, 4, 5 or 6; and
R1 is selected from the group consisting of (a) alkyl; (b) C3 to C8 cycloalkyl; (c) phenyl or substituted phenyl; (d) heterocyclic; (e) decahydronaphthalene and (f) octahydroindane; or
R1 and X may be taken together to denote a 5,6 or 6,6 saturated bicyclic ring structure when X can be NH, O, or S.
Preferably, the present invention provides compounds of the general formula: 
where
R2 and R3 are H, methyl or ethyl;
A is xe2x80x94NHCH2xe2x80x94, xe2x80x94N(CH3)xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94COCHxe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH(OH)CH2xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94;
X is H, CH3, NH2, NH(CH3), N(CH3)2, OH, OCH3 or SH;
R2 is hydrogen or a methyl or ethyl group;
R3 is hydrogen or a methyl or ethyl group;
n is 0, 1, 2, 3, 4, 5 or 6; and
R1 is selected from the group consisting of of (a) alkyl; (b) C3 to C8 cycloalkyl; (c) phenyl or substituted phenyl; (d) heterocyclic; (e) decahydronaphthalene and (f) octahydroindane; or
R1 and X may be taken together to denote a 5,6 or 6,6 saturated bicyclic ring structure when X can be NH, O, or S.
More preferably, the present invention provides compounds of the general formula: 
where
A is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94;
X is H or NH2;
R2 and R3 are H;
n is 1, 2, 3, 4 or 5; and
R1 is selected from the group consisting of (a) alkyl; (b) C3 to C8 cycloalkyl and (c) phenyl or substituted phenyl; (d) heterocyclic; (e) decahydronaphthalene and (f) octahydroindane.
Most preferably, the present invention provides compounds of the general formula: 
where
A is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94;
X is H or NH2;
R2 and R3 are H;
n is 1, 2, 3, 4 or 5;
R1 is selected from the group consisting of (a) alkyl; (b) C3 to C8 cycloalkyl and (c) phenyl or substituted phenyl.
The present invention is also directed to compounds that are useful in the preparation of compounds of formula (1.0).
These intermediates are compounds of the formula: 
where R4 is xe2x80x94H, triphenylmethyl, 2-(trimethylsilyl)ethoxymethyl (SEM), xe2x80x94SO2N(Me)2, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), or other known Nxe2x88x921 imidazole protecting groups; and
Z is (CH2)aB where a is 0,1, 2, 3 or 4 and B is 
xe2x80x83and each R5 can independently be Cl, Br, I or H.
The pharmaceutically acceptable salts, and individual stereoisomers of compounds of structural formula (1.0) above, as well as mixtures thereof, are also contemplated as falling within the scope of the present invention.
Representative compounds of this invention include compounds of the formulae (2.0 through 11.0): 
Particularly preferred compounds include: 
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers and diastereoisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
The compounds of formula (1.0) can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like are equivalent to the unsolvated forms for the purposes of the invention.
Certain compounds of the invention also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the nitrogen atoms may form salts with acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous hydroxide, potassium carbonate, ammonia, and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid salts are equivalent to their respective free base forms for purposes of the invention. (See, for example S. M. Berge, et al.,xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein by reference.
As throughout this specification and appended claims, the following terms have the meanings ascribed to them:
The term xe2x80x9calkylxe2x80x9d as used herein refers to straight or branched chain radicals derived from saturated hydrocarbons by the removal of one hydrogen atom. These radicals may be unsubstituted or substituted with one or more groups such as halogen, amino, methoxy, or similar groups. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, trifluoromethyl and the like.
The term xe2x80x9cheterocyclicxe2x80x9d as used herein refers to a closed-ring structure in which one or more of the atoms in the ring is an element other than carbon. Representative groups are preferably saturated and include pyrrolidines, tetrahydrofuranes, tetrahydrothiophenes, tetrahydro-isoquinolines and octahydroindole groups.
The term xe2x80x9csubstituted phenylxe2x80x9d as used herein refers to a phenyl group substituted by one or more groups such as alkyl, halogen, amino, methoxy, and cyano groups.
Individual enantiomeric forms of compounds of the present invention can be separated from mixtures thereof by techniques well known in the art. For example, a mixture of diastereoisomeric salts may be formed by reacting the compounds of the present invention with an optically pure form of the acid, followed by purification of the mixture of diastereoisomers by recrystallization or chromatography and subsequent recovery of the resolved compound from the salt by basification. Alternatively, the optical isomers of the compounds of the present invention can be separated from one another by chromatographic techniques employing separation on an optically active chromatographic medium.
The present invention also provides pharmaceutical compositions which comprise one or more of the compounds of formula (1.0) above formulated together with one or more nontoxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specifically formulated for oral administration in solid or liquid form, parental injection or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically as by being within the scope of this invention.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents and emulsifying agents.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay and i) lubricants such as calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976) p.33 et seq.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also comtemplated as being within the scope of the invention.
The following processes and techniques may be employed to produce compounds of formula (1.0). The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present in the molecule must be consistent with the chemical transformation proposed. This will frequently necessitate judgement as to the order of synthetic steps, protecting groups required and deprotection conditions.
A. PREPARATION OF COMPOUNDS WHEREIN A IS xe2x80x94CONHxe2x80x94 OR CONCH3xe2x80x94
According to the foregoing reaction scheme I, the N-tert-butoxycarbonyl (BOC), protected amino acid (Natural configuration) 1 is reacted with histamine or N-methyl histamine (2) under standard peptide coupling conditions using 1,3-dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT). After the reaction is complete (tic or hpic analysis), the amide (3) is treated with trifluoroacetic acid or HCl in dioxane to remove the BOC group and provide the histamine or N-methyl histamine amide (4).
B. PREPARATION OF COMPOUNDS WHEREIN A IS xe2x80x94NHCH2xe2x80x94 OR xe2x80x94N(CH3)CH2xe2x80x94
According to the foregoing reaction scheme II, the histamine or N-methylhistaminecarboxamide (4), prepared as described in scheme I, is treated with excess borane-methyl sulfide complex to provide histamine or N-methylhistamine diamine (5).
C. PREPARATION OF COMPOUNDS WHEREIN A IS xe2x80x94CH(OH)CH2xe2x80x94
According to the foregoing reaction scheme III, 3-(1-triphenylmethyl-1H-imidazol-4-yl)-propanal (6) is treated with the dianion of sulphone (7), prepared by the reaction of the sulphone with strong base, (n-BuLi) at xe2x88x9278xc2x0 C. The diastereoisomeric mixture of beta-hydroxy-sulphones (8) produced, is treated with excess Raney nickel (W-2) at room temperature to give a mixture of alcohols (9). The trityl protecting group is removed, as previously described, to provide the [1H-imidazol-4-yl]-amino alcohols (10).
D. PREPARATION OF COMPOUNDS WHEREIN A IS xe2x80x94CHxe2x95x90CH-(trans-olefins) 
According to the foregoing reaction scheme IV, the diastereoisomeric mixture of beta-hydroxy sulphones (8) synthesized as described in scheme III, is treated with excess 2-3% Na(Hg) in methanol in the presence of 4 equivalents of sodium hydrogen phosphate buffer to provide the 3-[1-triphenylmethyl-1H-imidazol-4-yl]-trans-olefin (11). Subsequent BOC and trityl deprotection with HCl gives 3-[1H-imidazol-4-yl]-trans-olefin (12).
E. PREPARATION OF COMPOUNDS WHEREIN A IS xe2x80x94Cxe2x89xa1Cxe2x80x94
According to the foregoing reaction scheme V, the 3-[1-triphenylmethyl-1H-imidazol-4-yl]-3-keto sulfone (13), is treated with NaH in THF, followed by reaction with diethyl chlorophosphate to give the enol phosphates (14). The enol phosphates are reduced with excess Sml2 in dry THF and 4 mole % hexamethylphosphoramide (HMPA) to provide the 3-[1-triphenylmethyl-1H-imidazol-4-yl]-acetylene (15). Finally, deprotection of the trityl group with HCl gives 3-[1H-imidazol-4-yl]-acetylenes (16).
F. PREPARATION OF COMPOUNDS WHEREIN A IS xe2x80x94CHxe2x95x90CHxe2x80x94(cis-olefins) 
According to the foregoing reaction scheme VI, 3-[1-triphenylmethyl-1H-imidazol-4-yl]-acetylene (15), prepared as in scheme V is hydrogenated with Lindlar catalyst to afford 3-[1-triphenylmethyl-1H-imidazol-4-yl]-cis-olefin (17). The trityl group is deprotected with HCl to afford 3-1H-imidazol-4-yl]-cis-olefin (18).
G. PREPARATION OF COMPOUNDS WHEREIN A IS xe2x80x94COCH2xe2x80x94
According to the foregoing reaction scheme VII, condensation of the sulfone anion derived from (20) (treatment with n-BuLi at xe2x88x9278xc2x0 C., 2.5 equivalents of sulfone: 1 equivalent of methyl ester) with the methyl ester (19) provides 3-[1-triphenylmethyl-1H-imidazol-4-yl]-3-keto sulfone (13). Treatment of ketosulfone (13) with Al(Hg) gives 3-[1-triphenylmethyl-1H-imidazol-4-yl]-ketone (21). Trityl deprotection with HCl gives 3-[1H-imidazol-4-yl]-ketones (22).
H. PREPARATION OF COMPOUNDS WHEREIN A IS xe2x80x94CH2CH2xe2x80x94
According to the foregoing reaction scheme VII, the 3-[1-triphenylmethyl-1H-imidazol-4-yl]-trans-olefin (15) is subjected to catalytic hydrogenation under the conditions described by Zervas et al., J. Am. Chem. Soc., 78, 1359 (1956), to reduce the carbon-carbon double bond and deprotect the trityl group, and provide the [1H-imidazol-4-yl]-alkane (23).
Histamine H3 receptor ligands having the general formula (24) were prepared from the key intermediate 4-1H-imidazol-4-yl]-1-butyne (26). 
This intermediate (26) is available from aldehyde (6) following either of two synthetic pathways outlined in scheme IX. Preparation of the vinyl dibromide (25) by the standard treatment with triphenylphosphine and carbon tetrabromide is quite tedious due to problems of triphenylphosphine oxide separation. The three step preparation of (25) from (6) gave comparable overall yields (70%). Treatment of vinyl dibromide (25) with an excess of n-BuLi gave the terminal acetylene (26) (90%). The acetylenes were obtained by alkylation of (26) followed by deprotection of the trityl group as shown in scheme X. 
Reagents (a) PPh3, CBr4; (b) Dibromomethane, Lithium dicyclohexylamide, xe2x88x9278xc2x0 C., THF; (c) MsCl, TEA, THF, 0xc2x0 C.; (d) TEA, THF, room temperature; (e) 2 equiv. n-BuLi, THF, xe2x88x9278xc2x0 C.
Alkylation of the terminal acetylene (26) were obtained with reactions performed using n-BuLi:N,N,N1,N1-tetramethylethylenediamine (TMEDA) complex in tetrahydrofuran at 55xc2x0 C. for 24-36 hours (Scheme X). 
Reagents: (a) n-BuLi:TMEDA, R-I, 55xc2x0 C., 24 hr; (b) 1N HCl, EtOH, 90xc2x0 C., 1 hr
The present invention is further illustrated by the following representative examples: